Refractory Partial Epilepsy
Conditions
Keywords
refractory, partial, epilepsy
Brief summary
This was a phase III 4-part study in multiple centres. Part I was a 26-week parallel-group, randomised, placebo-controlled period (8 weeks single-blind placebo baseline, 2 weeks double-blind titration, 12 weeks maintenance, and 4 weeks tapering off). After completing the baseline period, patients were randomised in a 1:1:1:1 ratio to 1 of 3 ESL dose levels or to placebo. Part II was a 1-year open-label extension for patients who had completed Part I. The starting dose was 800 mg once daily and could be titrated up or down at 400-mg intervals between 400 and 1200 mg. Part III was an additional 1-year open-label extension for patients who had completed Part II, had participated in the post-Part II study extension, which allowed patients to continue treatment with ESL, or had continued to take ESL in a compassionate use program. ESL starting doses were the same as received at the end of Part II, during post-Part II study extension, or under compassionate use, and could be titrated up or down at 400-mg intervals between 400 and 1200 mg once daily. Part IV was a study extension to allow patients to continue ESL treatment after the end of Part III until marketing authorisation or discontinuation of clinical development.
Detailed description
Duration of Treatment: The duration of Part I was 26 weeks: 8 weeks of placebo run-in, 2 weeks of dose titration, 12 weeks of maintenance, and 4 weeks of tapering-off period. The duration of Part II was 1 year. The duration of Part III was planned to be 1 year (some patients were treated for \>1 year). The duration of Part IV was \>3 years (patients could continue treatment with ESL until market availability).
Interventions
once-daily oral tablet
DRUGplacebo
once daily placebo comparator
Sponsors
Bial - Portela C S.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* written informed consent signed by patient * aged 18 years or more * documented diagnosis of simple or complex partial seizures with or without secondary generalisation since at least 12 months prior to screening * at least 4 partial seizures in each 4 week period during the last 8 weeks prior to screening, currently treated with 1 or 2 AEDs (any except oxcarbazepine and felbamate), in a stable dose regimen during at least 2 months prior to screening (patients using vigabatrin should have been on this medication for at least 1 year with no deficit in visual field identified) * excepting epilepsy, patient is judged to be in general good health based on medical history, physical examination and laboratory tests * post-menopausal or otherwise incapable of becoming pregnant by reason of surgery or tubal ligation; in case of woman of childbearing potential, patient must present a serum beta-hCG test consistent with a non-gravid state and agree to remain abstinent or use reliable contraception (oral contraception should be combined with a barrier method)
Exclusion criteria
* only simple partial seizures with no motor symptomatology (classified as A2-4 according to the International Classification of Epileptic Seizures) that are not video-EEG documented * primarily generalised epilepsy * known rapid progressive neurological disorder; history of status epilepticus or cluster seizures (i.e., 3 or more seizures within 30 minutes) within the 3 months prior to screening * seizures of psychogenic origin within the last 2 years * history of schizophrenia or suicide attempt * currently on or with exposure to felbamate or oxcarbazepine more within one month of screening * using benzodiazepines on more than on an occasional basis (except when used chronically as AED) * previous use of ESL or participation in a clinical study with ESL * known hypersensitivity to carbamazepine, oxcarbazepine or chemically related substances * history of abuse of alcohol, drugs or medications within the last 2 years * uncontrolled cardiac, renal, hepatic, endocrine, gastrointestinal, metabolic, haematological or oncology disorder * second or third-degree atrioventricular blockade not corrected with a pacemaker * relevant clinical laboratory abnormalities
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part I: Seizure Frequency | 12-week maintenance period | The primary efficacy endpoint is the natural log transformation of the seizure frequency per 4 weeks. The primary efficacy analysis was based on the intention-to-treat (ITT) population. Efficacy analyses were performed chiefly using data from the 12-week maintenance period in Part I of the study. The primary efficacy variable is the ln transformation of the seizure frequency per 4 weeks. Seizure frequency was compared between each active treatment group and the placebo group using an ANCOVA that models seizure frequency as a function of baseline seizure frequency and treatment.to a frequency per 4 weeks basis |
Countries
Portugal
Participant flow
Recruitment details
Study initiation date: 15/July/2004(first visit of the first patient) Study Part I completion date: 09/November/2005(last Part I visit of the last patient) Study Part II initiation date: 11 JAN 2005 (first Part II visit of the first patient) Study Part II completion date: 04 JAN 2007 (last Part II visit of the last patient)
Pre-assignment details
After completing the baseline period, patients were randomised in a 1:1:1:1 ratio to 1 of the 3 Eslicarbazepine acetate (ESL) dose levels or to placebo. Part II was a 1-year open-label extension for patients who had completed Part I
Participants by arm
| Arm | Count |
|---|---|
| ESL 1200 mg 400-mg + 800-mg; once daily administration by oral route | 102 |
| ESL 800 mg 800-mg; once daily administration by oral route | 98 |
| ESL 400 mg 400-mg; once daily administration by oral route | 100 |
| Placebo Placebo tablets; once daily administration by oral route | 102 |
| Total | 402 |
Baseline characteristics
| Characteristic | ESL 1200 mg | ESL 800 mg | ESL 400 mg | Placebo | Total |
|---|---|---|---|---|---|
| Age, Customized <=18 years | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Age, Customized >70 years | 0 participants | 2 participants | 1 participants | 0 participants | 3 participants |
| Age, Customized Between 18 and 70 years | 102 participants | 96 participants | 99 participants | 102 participants | 399 participants |
| Sex: Female, Male Female | 57 Participants | 44 Participants | 49 Participants | 54 Participants | 204 Participants |
| Sex: Female, Male Male | 45 Participants | 54 Participants | 51 Participants | 48 Participants | 198 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 62 / 102 | 27 / 100 | 49 / 98 | 14 / 102 |
| serious Total, serious adverse events | 3 / 102 | 9 / 100 | 4 / 98 | 3 / 102 |
Outcome results
Primary
Part I: Seizure Frequency
The primary efficacy endpoint is the natural log transformation of the seizure frequency per 4 weeks. The primary efficacy analysis was based on the intention-to-treat (ITT) population. Efficacy analyses were performed chiefly using data from the 12-week maintenance period in Part I of the study. The primary efficacy variable is the ln transformation of the seizure frequency per 4 weeks. Seizure frequency was compared between each active treatment group and the placebo group using an ANCOVA that models seizure frequency as a function of baseline seizure frequency and treatment.to a frequency per 4 weeks basis
Time frame: 12-week maintenance period
Population: The primary efficacy analysis was based on the ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Part I: Seizure Frequency | 7.64 ln (Seizures) per 4 weeks | 95% Confidence Interval 0.0563 |
| ESL 400 mg | Part I: Seizure Frequency | 6.73 ln (Seizures) per 4 weeks | 95% Confidence Interval 0.0563 |
| ESL 800 mg | Part I: Seizure Frequency | 5.66 ln (Seizures) per 4 weeks | 95% Confidence Interval 0.0558 |
| ESL 1200 mg | Part I: Seizure Frequency | 5.35 ln (Seizures) per 4 weeks | — |